Structural and reactivity studies on the ternary system guanine/methionine/trans-[PtCl2(NH3)L] (L = NH3, quinoline): implications for the mechanism of action of nonclassical trans-platinum antitumor complexes

The present model study explores the chemistry of methionine complexes and ternary methionine-guanine adducts formed by trans-[PtCl2(NH3)(2)] (1) and antitumor trans-[PtCl2(NH3)quinoline] (2) using 1D (H-1, Pt-195) and 2D NMR spectroscopy. Compound 2 was substitution inert in reactions with N-acetyl -L-methionine [AcMet(H)]. Reactions of trans [PtCl(NO3)(NH3)quinoline] (5) ("monoactivated" 2) with AcMetH in water and acetone at various stoichiomet ries point to Pt(II)-S binding that requires prior activation of the Pt-Cl bond by labile oxygen donors. Trans-[PtCl{AcMet(H)-S}(NH3)quinoline] (NO3) (6) and trans-[Pt{AcMet(H)-S}(2)(NH3)quinoline] (NO3)(2) (7) were isolated from these mixtures. At high [Cl-], AcMet(H) is displaced from 7, giving 6. Frozen stereodynamics in 6 at the thioether-S and dow rotation about the P t-N-quinoline bond result in four spectroscopically distinguishable diaster eomers. H-1 NMR spectra of 7 show faster exchange dynamics due to mutual tr anslabilization of the sulfur donors. Substitution of chloride in trans-[Pt Cl(9-EtGua)(NH3)L]NO3 (L = NH3, 3; L = quinoline, 4; 9-EtGua = 9-ethylguani ne, which mimics the first DNA binding step of 1 and 2) by methionine-sulfu r proceeded ca. 2.5 times slower for the quinoline compound. Both reactions , in turn, proved to be ca. 4 times faster than binding of a second nucleob ase under analogous conditions. From the resulting mixtures the ternary add ucts trans-[Pt(AcMet-S)(9-EtGua-N7)(NH3)L](NO3, Cl) (L = NH3, 8; L = quinol ine, 9) were isolated. A species analogous to 9 formed in a rapid reaction between 6 and 5'-guanosine monophosphate (5'-GMP). From NMR data an AMBER-b ased solution structure of the resulting adduct, trans-[Pt(AcMet-S)(5'-GMP- N7)(NH3)quinoline] (10), was derived. The unusual reactivity along the N7-P t-S axis in 8-10 resulted in partial release of both 9-EtGua and AcMet at h igh [Cl-]. Possible consequences of the kinetic and structural effects (e.g ., trans effect of sulfur, steric demand of quinoline) observed in these sy stems with respect to the (trans)formation of potential biological cross-li nks are discussed.